Genetic mechanisms of fertilization failure and early embryonic arrest: a comprehensive review

Abstract

BACKGROUND Infertility and pregnancy loss are longstanding problems. Successful fertilization and high-quality embryos are prerequisites for an ongoing pregnancy. Studies have proven that every stage in the human reproductive process is regulated by multiple genes and any problem, at any step, may lead to fertilization failure (FF) or early embryonic arrest (EEA). Doctors can diagnose the pathogenic factors involved in FF and EEA by using genetic methods. With the progress in the development of new genetic technologies, such as single-cell RNA analysis and whole-exome sequencing, a new approach has opened up for us to directly study human germ cells and reproductive development. These findings will help us to identify the unique mechanism(s) that leads to FF and EEA in order to find potential treatments. OBJECTIVE AND RATIONALE The goal of this review is to compile current genetic knowledge related to FF and EEA, clarifying the mechanisms involved and providing clues for clinical diagnosis and treatment. SEARCH METHODS PubMed was used to search for relevant research articles and reviews, primarily focusing on English-language publications from January 1978 to June 2023. The search terms included fertilization failure, early embryonic arrest, genetic, epigenetic, whole-exome sequencing, DNA methylation, chromosome, non-coding RNA, and other related keywords. Additional studies were identified by searching reference lists. This review primarily focuses on research conducted in humans. However, it also incorporates relevant data from animal models when applicable. The results were presented descriptively, and individual study quality was not assessed. OUTCOMES A total of 233 relevant articles were included in the final review, from 3925 records identified initially. The review provides an overview of genetic factors and mechanisms involved in the human reproductive process. The genetic mutations and other genetic mechanisms of FF and EEA were systematically reviewed, for example, globozoospermia, oocyte activation failure, maternal effect gene mutations, zygotic genome activation abnormalities, chromosome abnormalities, and epigenetic abnormalities. Additionally, the review summarizes progress in treatments for different gene defects, offering new insights for clinical diagnosis and treatment. WIDER IMPLICATIONS The information provided in this review will facilitate the development of more accurate molecular screening tools for diagnosing infertility using genetic markers and networks in human reproductive development. The findings will also help guide clinical practice by identifying appropriate interventions based on specific gene mutations. For example, when an individual has obvious gene mutations related to FF, ICSI is recommended instead of IVF. However, in the case of genetic defects such as phospholipase C zeta1 (PLCZ1), actin-like7A (ACTL7A), actin-like 9 (ACTL9), and IQ motif-containing N (IQCN), ICSI may also fail to fertilize. We can consider artificial oocyte activation technology with ICSI to improve fertilization rate and reduce monetary and time costs. In the future, fertility is expected to be improved or restored by interfering with or supplementing the relevant genes.

Influencing factors of fertilization failure during in vitro fertilization

“…In addition to the clinical characteristics of patients, complete FF may also be induced by genetic defects. NF can be achieved in some cycles through ICSI [19], and some cycles, however, require ICSI combined with arti cial oocyte activation [20], which was not discussed in the present study.…”

Novel Nuclear Roles for Testis-Specific ACTL7A and ACTL7B Supported byIn VivoCharacterizations and AI FacilitatedIn SilicoMechanistic Modeling with Implications for Epigenetic Regulation in Spermiogenesis

“…However, if the hypothetical courses of events caused by acrosomal instability were found true, it could affect a significant number of men with acrosomal defects and be categorized as a novel contributor to male infertility. Many human polymorphisms have been recently reported of single-point coding mutation in subacrosomal proteins like ACTL7A, ACTL7C, and ACTRT1 (Xin et al, 2020;Wei, Wang, et al, 2023;Zhou et al, 2023;Sha et al, 2021) that lead to both male infertility and peeling acrosomes. If the presented transcription changes in Actl7b -/-testes were caused in part by the exposure to acrosomal contents leading to accompanied inflammation, immune, and apoptotic responses, then a similar hypothesized pathology would be expected in men with these polymorphisms.…”

Early rescue oocyte activation at 5 h post-ICSI is a useful strategy for avoiding unexpected fertilization failure and low fertilization in ICSI cycles

“…Therefore, we recommend determining an optimal time point based on real data from one’s own laboratory before performing EROA, which is very useful for standardized clinical applications. On the other hand, the pathophysiological mechanisms of fertilization disorders are complex, and genetic defects in sperm or oocytes from infertile couples are also important factors leading to fertilization failure ( 24 , 29 , 30 ), which may not be resolved in these patients just with oocyte activation treatment. The present study did not conduct genetic testing for infertile couples, which might lead to some limitations in the study conclusions.…”